Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology.

Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6-10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is currently focused on the potential role of genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the transforming growth factor-beta (TGF-ß) pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future, as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield reliable results that will allow a better understanding of SCD-related PH as a part of the disease's clinical spectrum. This review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.

Peripheral Neuropathy in Patients with Hepatitis C Infection-Reversibility after HCV Eradication: A Single Center Study.

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement.

High-Oxygen-Affinity Hemoglobins-Case Series and Review of the Literature.

Modifications of the hemoglobin (Hb) structure in regions involving the regulation of oxygen transport may lead to an increased oxygen affinity for the hemoglobin molecule and impaired oxygen delivery to the tissues. Herein, we present six patients with high-oxygen-affinity Hb variants, either in heterozygous form or in compound heterozygosity (such as heterozygosity for Hb Hiroshima, Köln, Crete, and compound heterozygosity Hb Crete with ß or 뫧 thalassemia), in order to demonstrate the need for prompt and accurate diagnosis and enrich the limited literature due to the rarity of such cases. Hb Crete, Hb Hiroshima, and Hb Köln have distinct pathophysiologies and may result in different clinical phenotypes. In conclusion, high-oxygen-affinity hemoglobins are rare and inherited within a dominant autosomal manner, have various clinical presentations, and should always be suspected in patients with erythrocytosis. Their management (as phlebotomy or low-dose aspirin) should be based on an individualized assessment of the risk of complications, the medical history, concomitant symptoms, and quality of life.

The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. METHODS: In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. RESULTS: Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. CONCLUSION: In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.

Gaucher-like Cells in Thalassemia Intermedia: Is It a Challenge?

We describe two cases of thalassemia intermedia (TI) patients with the presence of Gaucher-like cells in hematopoietic tissue biopsies, raising diagnostic dilemmas. The first is a 56-year-old female with bone lesions, splenomegaly, hypochromic microcytic anemia and Gaucher-like cells in the bone marrow, with a final diagnosis of TI, and the second is a 69-year-old male with TI, monoclonal gammopathy of undetermined significance (MGUS) that accelerated to multiple myeloma (MM) requiring treatment, bone disease and Gaucher-like cells in the bone marrow and the spleen, and heterozygoty of Gaucher disease (GD). Gaucher-like cells are difficult to differentiate from true Gaucher cells, that are the hallmark of GD suspicion. These cells are usually reported in the lymphohematopoietic system. They have been described in myeloproliferative disorders, hematological malignancies, infectious diseases, hemoglobinopathies and other hemolytic anemias. The presence of Gaucher-like cells in patients with thalassemia major has been well documented, whereas there are limited references regarding cases with thalassemia intermedia. The identification of these cells in thalassemia probably reflects the high cell turnover. The bony complications in GD and TIare not yet fully explained in the literature, and this raises the question of whether Gaucher-like cells could play a pathogenetic role in the bone disease of thalassemia, as Gaucher cells are considered to play a similar role in bone complications of GD. Moreover, given the rarity and similarity of Gaucher and Gaucher-like cells, we would like to highlight that the presence of Gaucher-like cells in the bone marrow should not be overlooked, as they might be obscuring an underlying pathology, in order to ensure that hematologists, internists and hematopathologists will be promptly and accurately diagnosed.

Case Report of Myelodysplastic Syndrome in a Sickle-Cell Disease Patient Treated with Hydroxyurea and Literature Review.

The safety profile of hydroxyurea (HU) in patients with sickle-cell disease (SCD) is relatively well known. However, despite the suspected association of HU with myeloid neoplasms in myeloproliferative neoplasms (MPN), and the publication of sporadic reports of myeloid malignancies in SCD patients treated with HU, the possible excess risk imparted by HU in this population having an increasing life expectancy has failed to be demonstrated. Herein, we report one case of myelodysplastic syndrome emanating from the results on safety and effectiveness of HU on the largest European cohort of 1903 HU-treated adults and children who were followed-up prospectively in an observational setting over 10 years, accounting for a total exposure of 7309.5 patient-years. A comparison of this single case with previously published similar cases did not allow us to draw any significant conclusions due to the paucity of these events.

Difficulties in Diagnosing and Treating Disseminated Bacillus Calmette-Guérin (BCG) Infection After Intravesical BCG Therapy in a Patient with Liver Cirrhosis: A Case Report.

BACKGROUND Bladder cancer (BC) is the second most common cancer involving the urinary system. In non-muscle-invading BC, transurethral resection of a bladder tumor followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) is the usual treatment. Disseminated (or systemic) BCG infection (BCGitis) represents the most severe adverse effect of intravesical BCG therapy, presenting with high-grade fever, with or without symptoms in the urinary tract, leading to severe sepsis and death if left untreated. The treatment of choice consists of isoniazid, rifampicin, and ethambutol (with or without corticosteroids) for 6 months, and the recovery rate is extremely high. Given the fact that these drugs are hepatotoxic, treating a patient with liver cirrhosis is challenging. CASE REPORT We present a patient with a medical history of BC treated with transurethral resection and intravesical BCG therapy, presenting with fever, transaminasemia, and generalized weakness. Liver and bone marrow biopsies revealed liver cirrhosis and granulomas in both organs. A diagnose of BCGitis was made and the patient was treated with isoniazid, rifampicin, and ethambutol; rifampicin was substituted with moxifloxacin after 1 month due to worsening of liver laboratory results, and moxifloxacin was substituted with levofloxacin later on due to tonic-clonic seizures. The patient was treated for 4 more months with levofloxacin and for 7 more months with isoniazid and ethambutol, with no other adverse effects, preserving liver function and achieving cure of BCGitis. CONCLUSIONS We present the case of a cirrhotic patient presenting with fever and deterioration of liver laboratory results, found to have BCGitis, and discuss possible difficulties in diagnosing and treating such patients.

Outcomes of pregnancies in patients with Gaucher Disease: The experience of a center of excellence on rare metabolic Disease-Gaucher Disease, in Greece.

OBJECTIVE: Pregnancy is reported to exacerbate manifestations in women with Gaucher Disease (GD). The objective of our study was to examine the outcome of pregnancies of Caucasian women with GD in a Greek Center of Excellence on GD. STUDY DESIGN: Fifteen GD women were enrolled. All data were collected by questionnaire: fertility, normal pregnancies, spontaneous-elective-therapeutic abortions, maternal -neonatal status, birth weight and chromosomal abnormalities. RESULTS: Forty-one pregnancies were reported among 15 women: mean conception age (±SD) 27.7 ±â€¯5.8years (range 17-42years). Thirty-seven conceptions were spontaneous, 4 were after in vitro fertilization (IVF). Twenty three out of the 41 (56.1 %) pregnancies were normal. Eleven out of the 41 (26.8 %) pregnancies resulted in spontaneous abortions, 3 out of 41 (7.3 %) in elective and 3 out of 41 (7.3 %) in therapeutic abortions. Therapeutic abortions were due to worsening of GD manifestations, fetal chromosomal abnormalities and GD type 2 embryo. Nine out of 15 women had maternal complications: gestational diabetes, splenomegaly, hepatomegaly, thrombocytopenia, osteoporosis and postpartum hemorrhage. Twenty three out of the 41 pregnancies resulted in live births. Nine out of the 23 (39.1 %) deliveries were caesarian sections and 14 out of 23 (60.9 %) were vaginal. The total number of neonates was 24 (14 females / 10 males). Mean gestational age on delivery (± SD) was 35.9 ±â€¯3.1 weeks (range 26-38 w). Average female birth weight (±SD) was 2671.4 ±â€¯851.6 g (range 900-4100 grams) and male was 3333 ±â€¯996.4 g (range 1930-4700 grams). Nine out of 24 (37.5 %) neonates had low birth weight. Average low birth weight (±SD) was 1931.1 ±â€¯420.52 g (range 900-2300 grams). Twenty out of the 24 (83.3 %) neonates were healthy. Four out of 24 neonates had neonatal complications: two neonates had GD type 1, one had GD type 3 and one neonate died two days after delivery (it was born at 26 weeks). Four neonates were hospitalized in incubators at the intensive neonatal care unit due to low birth weight. Thirty-nine women did not receive enzyme replacement therapy for GD during pregnancy, while, in two pregnancies, treatment was discontinued during the first trimester and re-administered after that. Mean first menarche age (±SD) was 13.6 ±â€¯0.7 years. Thirteen out of 15 women were menopausal, mean menopausal age (± SD) 466 ±â€¯2.6 years. CONCLUSION: Most of GD women experience uncomplicated pregnancies and deliver normal, healthy infants, although the rate of complications and the rate of abortions is high in this population.

The Growth Differentiation Factor-15 (GDF-15) levels are increased in patients with compound heterozygous sickle cell and beta-thalassemia (HbS/ßthal), correlate with markers of hemolysis, iron burden, coagulation, endothelial dysfunction and pulmonary hypertension.

The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. GDF-15, a multifactorial cytokine, is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury, while high levels of serum GDF-15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. In this context we aimed to evaluate GDF-15 levels in 89 patients with HbS/ßthal at steady phase and in 20 apparently healthy individuals, and correlate with clinical features of the disease and markers of hemolysis, iron burden, inflammation, coagulation and endothelial dysfunction. We found that: GDF-15 levels were elevated in patients with HbS/ßthal compared to controls (1980.7 ±â€¯159.8 vs 665.4 ±â€¯50.9 pg/mL, p < 0.0001) and correlated significantly with LDH (p < 0.001), Hepcidin-25/Ferritin molar ratio (p = 0.002), vWF:antigen (p < 0.05), HbA% (p < 0.001) and Mean Pulmonary Artery Pressure (p < 0.001). These findings demonstrate for first time an important multifactorial role of GDF-15 in patients with HbS/ßthal, however, prior to its clinical usefulness, this biomarker must undergo through rigorous validation in multiple cohorts.

Prognostic Implication of the Absolute Lymphocyte to Absolute Monocyte Count Ratio in Patients With Classical Hodgkin Lymphoma Treated With Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine or Equivalent Regimens.

Low absolute lymphocyte count (ALC) to absolute monocyte count (AMC) ratio (ALC/AMC) is an independent prognostic factor in Hodgkin lymphoma (HL), but different cutoffs (1.1, 1.5, and 2.9) have been applied. We aimed to validate the prognostic significance of ALC/AMC in 537 homogenously treated (doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalents ± radiotherapy) classical HL patients at various cutoffs. The median ALC/AMC was 2.24 (0.44-20.50). The median AMC was 0.653 × 10(9)/L (0.050-2.070). Lower ALC/AMC was associated with established markers of adverse prognosis. In total, 477 (89%), 418 (78%), and 189 (35%) patients had an ALC/AMC ratio of ≥1.1, ≥1.5, and ≥2.9; respectively; 20% had monocytosis (≥0.9 × 10(9)/L). Ten-year time to progression (TTP) was 77% versus 55% for patients with ALC/AMC ≥1.1 and <1.1 (p = .0002), 76% versus 68% for ALC/AMC ≥1.5 and <1.5 (p = .049), 77% versus 73% for ALC/AMC ≥2.9 and <2.9 (p = .35), and 79% versus 70% for ALC/AMC ≥2.24 and <2.24 (p = .08), respectively. In stages ΙΑ/ΙΙΑ and in patients ≥60 years old, ALC/AMC had no significant effect on TTP. In advanced stages, ALC/AMC was significant only at the cutoff of 1.1 (10-year TTP 67% vs. 48%; p = .016). In younger, advanced-stage patients, the differences were more pronounced. In multivariate analysis of TTP, ALC/AMC < 1.1 (p = .007) and stage IV (p < .001) were independent prognostic factors; ALC/AMC was independent of International Prognostic Score in another model. ALC/AMC was more predictive of overall survival than TTP. At the cutoff of 1.1, ALC/AMC had independent prognostic value in multivariate analysis. However, the prognostically inferior group comprised only 11% of patients. Further research is needed prior to the widespread use of this promising marker.

Potential role of AKT/mTOR signalling proteins in hairy cell leukaemia: association with BRAF/ERK activation and clinical outcome.

The potential role of AKT/mTOR signalling proteins and its association with the Raf-MEK-ERK pathway was investigated in hairy cell leukaemia (HCL). BRAFV600E expression and activated forms of AKT, mTOR, ERK1/2, p70S6k and 4E-BP1 were immunohistochemically assessed in 77 BM biopsies of HCL patients and correlated with clinicopathological and BM microvascular characteristics, as well as with c-Caspase-3 levels in hairy cells. Additionally, we tested rapamycin treatment response of BONNA-12 wild-type cells or transfected with BRAFV600E. Most HCL cases expressed p-p70S6K and p-4E-BP1 but not p-mTOR, being accompanied by p-ERK1/2 and p-AKT. AKT/mTOR activation was evident in BONNA-12 cells irrespective of the presence of BRAFV600E mutation and was implicated in cell proliferation enhancement. In multivariate analysis p-AKT/p-mTOR/p-4E-BP1 overexpression was an adverse prognostic factor for time to next treatment conferring earlier relapse. When p-AKT, p-mTOR and p-4E-BP1 were examined separately only p-4E-BP1 remained significant. Our findings indicate that in HCL, critical proteins up- and downstream of mTOR are activated. Moreover, the strong associations with Raf-MEK-ERK signalling imply a possible biologic interaction between these pathways. Most importantly, expression of p-4E-BP1 alone or combined with p-AKT and p-mTOR is of prognostic value in patients with HCL.

Pure red cell aplasia complicating the course of long-standing mantle cell lymphoma.

Pure red cell aplasia (PRCA) is a rare cause of severe hypoplastic anemia characterized by profound depletion of erythroid precursors. Although PRCA may be associated with lymphoproliferative diseases, it has never been described in mantle cell lymphoma (MCL). We report what to our knowledge is the first case of a patient with indolent, non-nodal MCL complicated by PRCA. The patient presented with severe hypoproliferative anemia in the setting of a long-standing diagnosis of B-cell chronic lymphocytic leukemia. Bone marrow studies revealed the complete absence of erythroid progenitors. Cyclin D1 positivity on immunohistochemistry, confirmed by a positive FISH for t(11;14) (q13;q32), established the final diagnosis of MCL in conjunction with PRCA. Rituximab monotherapy led to rapid remission of splenomegaly and the leukemic picture, but the patient achieved transfusion independency only with subsequent administration of cyclosporine-A, and remained so during the subsequent 15 months despite the gradual disease recurrence.